Hollow microneedle with bevel opening

ABSTRACT

An article having at least one microneedle ( 160, 260 ) is provided. The microneedle includes a base ( 162 ), an elongated body ( 161 ) having a central axis ( 130 ) and a body diameter ( 168 ), a tip portion ( 166 ), a first channel ( 170 ), and a second channel ( 176 ). The tip portion includes a tip ( 164 ), a beveled surface ( 140 ), and a bevel opening ( 172 ) in the beveled surface. The first channel extends axially from the bevel opening through at least a portion of the elongated body and has a first wall that is substantially aligned with the central axis. The second channel extends radially from the first channel to the bevel opening and has a second wall that is oriented substantially orthogonal to the central axis. The first channel and second channel merge to form the bevel opening.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority of U.S. Provisional Patent ApplicationNo. 61/846,945, filed Jul. 16, 2013, the disclosure of which isincorporated by reference in its entirety herein.

BACKGROUND

Transdermal and topical drug delivery can be used for therapeutictreatment, but the number of molecules that can be effectively deliveredusing these routes can be limited by the barrier properties of skin. Themain barrier to transport of molecules through the skin is the stratumcorneum (the outermost layer of the skin).

A number of different skin treatment methods have been proposed in orderto increase the permeability or porosity of the outermost skin layers,such as the stratum corneum, thus enhancing drug delivery through orinto those layers. The stratum corneum is a complex structure of compactkeratinized cell remnants separated by lipid domains. The stratumcorneum is formed of keratinocytes, which comprise the majority ofepidermal cells that lose their nuclei and become corneocytes. Thesedead cells comprise the stratum corneum, which has a thickness of onlyabout 10-30 microns and protects the body from invasion by exogenoussubstances and the outward migration of endogenous fluids and dissolvedmolecules. Various skin treatment methods include the use ofmicroneedles, laser ablation, RF ablation, heat ablation, sonophoresis,iontophoresis, or a combination thereof.

Devices including arrays of relatively small structures, sometimesreferred to as microneedles or micro-pins, have been disclosed for usein connection with the delivery of therapeutic agents and othersubstances through the skin and other surfaces. The devices aretypically pressed against the skin in an effort to pierce the stratumcorneum such that the therapeutic agents and other substances cansequentially or simultaneously pass through that layer and into thetissues below. Microneedles of these devices pierce the stratum corneumupon contact, making a plurality of microscopic slits which serve aspassageways through which molecules of active components can bedelivered into the body. In delivering an active component, themicroneedle device can be provided with a reservoir for temporarilyretaining an active component in liquid form prior to delivering theactive component through the stratum corneum. In some constructions, themicroneedles can be hollow to provide a liquid flow path directly fromthe reservoir and through the microneedles to enable delivery of thetherapeutic substance through the skin. In alternate constructions,active component(s) may be coated on the microneedle array and delivereddirectly through the skin after the stratum corneum has been punctured.

Microneedle arrays can be used in conjunction with an applicator devicecapable of being used several times or as a single-use device. Themicroneedle arrays are generally used once and then discarded.

SUMMARY

The present inventors recognized that issues related to applyingmicroneedles include the ability to effectively and consistently insertthe needles to a desired depth in the skin, the ability to reliably holdthe microneedles in proper contact with the skin during the period ofadministration, and the ability to apply consistent force for delivery.

The present disclosure generally relates to articles comprising one ormore hollow microneedles. In particular, the present disclosure providesa hollow microneedle with an opening that is configured to facilitatethe delivery of material from the hollow microneedle into tissue (e.g.,skin tissue). In addition, the present disclosure provides a method ofmaking hollow microneedles.

Some aspects of the present disclosure provide an article. The articlecan comprise at least one hollow microneedle. The at least onemicroneedle can comprise a base, an elongated body having a centralaxis, a tip portion, a first channel, and a second channel. The tipportion can comprise a tip, a beveled surface, and a bevel opening inthe beveled surface. The first channel can extend axially from the bevelopening through at least a portion of the elongated body, wherein thefirst channel has a first wall that is substantially aligned with thecentral axis. The second channel can extend radially from the firstchannel to the bevel opening, wherein the second channel has a secondwall that is oriented substantially orthogonal to the central axis. Thefirst channel and second channel merge to form the bevel opening.

Other aspects of the present disclosure provide a method of making anarticle comprising at least one microneedle. The microneedle cancomprise an elongated body having body diameter, a base, a tip portion,and a hollow channel extending from the base to the tip portion. Themethod can comprise providing a first mold half comprising at least onecavity; wherein the at least one cavity includes a cavity opening and acavity surface having a first projection extending therefrom toward thecavity opening; wherein the first projection defines a first segment ofthe hollow channel, the first segment extending into the body of themicroneedle from the base; wherein the first projection comprises afirst longitudinal axis. The method further can comprise providing asecond mold half comprising at least one second projection extendingtherefrom; wherein the at least one second projection defines a tipportion of the microneedle and a second segment of the hollow channel,the second segment extending into the body of the microneedle from abevel opening proximate the tip of the at least one microneedle; whereinthe at least one second projection comprises a second longitudinal axis;wherein the second projection is shaped and dimensioned to define thetip portion; wherein the tip portion includes a tip, a beveled surface,a bevel opening in the bevel surface, a first channel that extendsaxially from the bevel opening through at least a portion of theelongated body, and a second channel that extends radially from thefirst channel to the bevel opening; wherein the first channel has afirst wall that is substantially aligned with the second longitudinalaxis; wherein the second channel has a second wall that is orientedsubstantially orthogonal to the second longitudinal axis; wherein thesecond projection is shaped and dimensioned such that the first channeland second channel merge to form the bevel opening. The method furthercan comprise contacting at least the first mold surface or the secondmold surface with moldable material and inserting the second projectioninto the at least one cavity.

The phrase “injection apparatus” refers to an integrated device capableof delivering or extracting a fluid over a certain period and is notlimited to devices intended solely for an infusion. Accordingly, aninjection apparatus may be used, for example, for injecting fluid intothe dermis or extracting fluid from tissue.

The term “transdermally” and variations thereof, is generally used torefer to any type of delivery of an active ingredient that crosses anyportion of skin. That is, transdermally can generally include systemicdelivery (i.e., where the active ingredient is transported across, orsubstantially through, the dermis such that the active ingredient isdelivered into the bloodstream), as well as intradermal delivery (i.e.,where the active ingredient is transported partially through the dermis,e.g., across the outer layer (stratum corneum) of the skin, where theactive ingredient is delivered into the skin, e.g., for treatingpsoriasis or for local anesthetic delivery). That is, transdermaldelivery as used herein includes delivery of an active ingredient thatis transported across at least a portion of skin (but not necessarilyall of the layers of skin), rather than merely being topically appliedto an outer layer of the skin.

The phrase “hollow microneedle” refers to a specific microscopicstructure that is designed for piercing the stratum corneum tofacilitate the delivery of drugs through the skin. By way of example,microneedles can include needle or needle-like structures, as well asother structures capable of piercing the stratum corneum and deliveringliquid drug formulations to skin or tissue layers beneath the stratumcorneum.

The words “preferred” and “preferably” refer to embodiments of theinvention that may afford certain benefits, under certain circumstances.However, other embodiments may also be preferred, under the same orother circumstances. Furthermore, the recitation of one or morepreferred embodiments does not imply that other embodiments are notuseful, and is not intended to exclude other embodiments from the scopeof the invention.

The terms “comprises” and variations thereof do not have a limitingmeaning where these terms appear in the description and claims.

As used herein, “a,” “an,” “the,” “at least one,” and “one or more” areused interchangeably. Thus, for example, a microneedle can beinterpreted to mean “one or more” microneedles.

The term “and/or” means one or all of the listed elements or acombination of any two or more of the listed elements.

Also herein, the recitations of numerical ranges by endpoints includeall numbers subsumed within that range (e.g., 1 to 5 includes 1, 1.5, 2,2.75, 3, 3.80, 4, 5, etc.).

The above summary of the present invention is not intended to describeeach disclosed embodiment or every implementation of the presentinvention. The description that follows more particularly exemplifiesillustrative embodiments. In several places throughout the application,guidance is provided through lists of examples, which examples can beused in various combinations. In each instance, the recited list servesonly as a representative group and should not be interpreted as anexclusive list.

Additional details of these and other embodiments are set forth in theaccompanying drawings and the description below. Other features, objectsand advantages will become apparent from the description and drawings,and from the claims.

BRIEF DESCRIPTION OF DRAWINGS

The present invention will be further explained with reference to thedrawing figures listed below, where like structure is referenced by likenumerals throughout the several views.

FIG. 1 is a perspective view of an embodiment of an article comprising ahollow microneedle.

FIG. 2 is a perspective view of an embodiment of a hollow microneedlecomprising a bevel face having an opening.

FIG. 3 is a perspective view of a mold part used to form a tip portionof the hollow microneedle of FIG. 2.

FIG. 4 is a perspective view of one embodiment of hollow microneedlehaving a bevel face with an opening according to the present disclosure.

FIG. 5 is a side view of the hollow microneedle of FIG. 4, showing thebevel face and the opening.

FIG. 6 is a side view of the hollow microneedle of FIG. 4, showing anoptional secondary bevel.

FIG. 7 is a top view of the hollow microneedle of FIG. 5.

FIG. 8 is a cross-sectional view of the hollow microneedle of FIG. 5,taken along line 8-8.

FIGS. 9A-B are side views of a mold part used to form a tip portion ofthe hollow microneedle of FIGS. 4-8.

FIG. 9C is a perspective view of the mold part of FIGS. 9A-B.

FIG. 10 is a schematic view of one embodiment of portions of mold partsthat are used in a molding process to make an article with a hollowmicroneedle according to the present disclosure.

FIG. 11 is a detail view of the tip portion of the microneedle of FIG.5, contrasting the area of a bevel opening of a conventional needle tipand the area of the bevel opening in a microneedle according to thepresent disclosure.

FIG. 12 is a detail view of the tip portion of the microneedle of FIG.5, showing an angle β formed by a secondary bevel and a plane that isaligned with the central axis of the microneedle.

DETAILED DESCRIPTION

Before any embodiments of the present disclosure are explained indetail, it is to be understood that the invention is not limited in itsapplication to the details of construction and the arrangement ofcomponents set forth in the following description or illustrated in thefollowing drawings. The invention is capable of other embodiments and ofbeing practiced or of being carried out in various ways. Also, it is tobe understood that the phraseology and terminology used herein is forthe purpose of description and should not be regarded as limiting. Theuse of “including,” “comprising,” or “having” and variations thereofherein is meant to encompass the items listed thereafter and equivalentsthereof as well as additional items. Unless specified or limitedotherwise, the terms “mounted,” “connected,” “supported,” and “coupled”and variations thereof are used broadly and encompass both direct andindirect mountings, connections, supports, and couplings. It is to beunderstood that other embodiments may be utilized, and structural orlogical changes may be made without departing from the scope of thepresent disclosure. Furthermore, terms such as “front,” “rear,” “top,”“bottom,” and the like are only used to describe elements as they relateto one another, but are in no way meant to recite specific orientationsof the apparatus, to indicate or imply necessary or requiredorientations of the apparatus, or to specify how the invention describedherein will be used, mounted, displayed, or positioned in use.

The present disclosure generally relates to articles comprising hollowmicroneedles having a tip portion that penetrates skin and provides anopening through which a composition (e.g., a pharmaceutically-activecompound) can be delivered into the skin tissue and other tissuedisposed in or underlying the skin tissue. In particular, the presentdisclosure relates to certain aspects of the tip portion that canprovide more-efficient delivery of compositions into the skin tissue. Inaddition, the aspects generally provide a more-robust method ofmanufacturing hollow microneedles and particularly provide a more-robustmethod of manufacturing high-aspect-ratio hollow microneedles.

Articles comprising hollow microneedles and/or hollow microneedle arraysare used, for example, to deliver compositions (e.g., compositionscomprising active ingredients). Such articles are described, forexample, in U.S. Pat. Nos. 8,088,321 and 8,246,893; and U.S. PatentApplication Publication Nos. US2011/0213335, US2012/0123387,US2012/0041337; and International Patent Publication No. WO2012/074576,which are all incorporated herein by reference in their entirety.

Turning to the drawings, FIG. 1 shows one embodiment of an article 100comprising at least one microneedle 160. In the illustrated embodiment,the article 100 comprises a circular-shaped array of a plurality ofmicroneedles 160. The article 100 comprises a unitary substrate 110having a first side 112 from which the microneedles 160 extend. In anyembodiment, an article according to the present disclosure can comprisea plurality of hollow microneedles. In any embodiment, the hollowmicroneedles can be arranged in an array (e.g., a regular array).Non-limiting examples of articles comprising hollow microneedles aredescribed in U.S. Provisional Patent Nos. 61/846,909 and 61/846,905filed on Jul. 16, 2013, which are both incorporated herein by referencein their entirety.

FIG. 2 shows one embodiment of a hollow microneedle 160. The microneedle160 comprises an elongated body 161 having at least one major surface163, central axis 130, a body diameter 168, a base 162 at one end of thebody 161, and a tip portion 166 at the other end of the body 161. Thebody 161 can take the form of a variety of shapes including, but notlimited to, cylindrical, conical, crateriform, pyramidal, andcombinations thereof. The tip portion 166 comprises a bevel face 140that extends diagonally, relative to the central axis, through the body161 and thereby forming the tip 164. As used herein, the “tip” of amicroneedle is a point of the microneedle that is farthest (as measuredalong the central axis) from the base of the microneedle. Preferably,the angle of the bevel face 140 with respect to the central axis 130 issufficiently acute such that it forms a sharp edge (e.g., forpenetrating skin) at the tip 164. The microneedle 160 further comprisesa hollow channel 170 that extends from the tip portion 166 into the body161 via a bevel opening 172 on the bevel face 140. Although illustratedas a relatively flat plane that is not coplanar with the at least onemajor surface of the microneedle, it is contemplated that, in anyembodiment, the bevel face in which the bevel opening is disposed may becoplanar with the at least one major surface of the microneedle (notshown).

It will be recognized by a person having ordinary skill in the art thatthe body diameter 168 of the microneedle 160 may vary along the centralaxis 130 of the microneedle, depending upon the shape of themicroneedle. The body diameter 168 shown in the illustrated embodimentcorresponds to the diameter of the microneedle 160 at the base 162.

FIG. 3 shows a perspective view of one embodiment of a mold part 150,referenced in the Examples as a “cylindrical projection”, which is usedto form the tip portion 166 of the hollow microneedle 160 of FIG. 2. Themold part 150 comprises a base 151. Generally, cross-sectional shape ofthe base will match the exterior shape of the tip portion to be formed.In the illustrated embodiment of FIG. 3, the base is cylindrical. Themold part further comprises a bevel-forming surface 153 and an extension154. The bevel-forming surface 153 defines the shape and angle of thebevel face of the microneedle. The extension 154 defines the shape(e.g., circular) and size of the opening in the bevel face and alsodefines the shape (e.g., cylindrical) and diameter of the hollow channelin the microneedle. In any embodiment, the microneedle may comprise ahollow channel that extends only partially through the body of themicroneedle (i.e., the hollow channel is a dead-end channel). In theseembodiments, the extension 154 may also define the depth of the hollowchannel that is made using the mold part 150.

FIGS. 4-8 show various views of one embodiment of a microneedle 260according to the present disclosure. Similar to the microneedle 160shown in FIG. 2, the microneedle 260 comprises an elongated body 161having at least one major surface 163, central axis 130, a body diameter168, a base 162 at one end of the body 161, and a tip portion 166 at theother end of the body 161. The tip portion 166 includes a bevel face 140with an opening 172 for a first channel 170 that extends axially intothe body 161 of the microneedle 260. The bevel face 140 is orienteddiagonally with respect to the central axis 130. The body 161 can takethe form of a variety of shapes including, but not limited to,cylindrical, conical, crateriform, pyramidal, and combinations thereof.

In contrast to the microneedle 160 of FIG. 2, the tip portion 166 of themicroneedle 260 comprises an opening 172 that is formed by a merging oftwo channels (i.e., first channel 170 and second channel 176. The firstchannel 170 has at least one wall 178 that is substantially aligned withthe central axis 130 of the microneedle 260. The second channel 176 hasat least one wall 177 that extends radially outward from the firstchannel 170. The at least one wall 177 of the second channel 176 isoriented substantially orthogonal to the central axis 130. The firstchannel 170 and the second channel 176 merge at the bevel face 140 toform the opening 172.

Preferably, the angle of the bevel face 140 with respect to the centralaxis 130 is sufficiently acute such that it forms a sharp edge (e.g.,for penetrating skin) at the tip 164. In the illustrated embodiment ofFIGS. 4-8, the tip 164 of the microneedle 260 is located at a pointwhere the bevel face 140 is farthest from the base 162 relative to thecentral axis.

In any embodiment, the bevel face 140 has a pitch (i.e., angle inrelation to the central axis of about 15° to about 40°. In a preferredembodiment, the bevel face 140 has a pitch of about 20° to about 35°. Ina more preferred embodiment, the bevel face 140 has a pitch of about 25°to about 33°.

The microneedle 260 further comprises a hollow channel 170 that extendsaxially into the body 161 from the tip portion 166 from a bevel opening172. The bevel opening 172 is defined by a first edge 174 of the face140. The bevel face 140 is defined by a second edge 149. In anyembodiment, no portion of the opening edge is coincident with anyportion of the bevel edge (e.g., the opening may approximately centeredwithin the area defined by the bevel face (not shown). Alternatively, inany embodiment, at least a portion of the first edge 174 is coincidentwith a portion of the second edge 149, as shown in FIG. 5. In theillustrated embodiment of FIG. 5, the bevel face 140 forms a surfacethat has the shape of a partial ellipse. The partial ellipse-shapedbevel face 140 substantially surrounds the opening 172.

In any embodiment, the tip portion 166 of the microneedle 260 optionallycomprises at least one secondary bevel 145. As shown in FIG. 5, thesecondary bevels 145 are used to form a sharp tip 164 that facilitatespenetration of skin by the microneedle 260. An angle (angle β, FIG. 12)can be used to define the angle of the secondary bevels 145. The angle βis defined by an intersection of a plane 132 that extends into theopening of the microneedle (through the central axis) and the edge ofthe microneedle tip created by the secondary bevel (see FIG. 12). In anyembodiment, the at least one secondary bevel has a pitch (i.e., an anglein relation to the plane 132, which is aligned with the central axis) ofabout 15° to about 40°. In a preferred embodiment, the bevel face 140has a pitch of about 25° to about 35°. In a more preferred embodiment,the bevel face 140 has a pitch of about 35° to about 35°.

FIGS. 9A-C show various views of one embodiment of a mold part 150′,referenced in the Examples as a “cylindrical projection”, which is usedto form the tip portion 166 of the hollow microneedle 260 of FIGS. 4-8.The mold part 150′ comprises a base 151. Generally, cross-sectionalshape of the base will match the exterior shape of the tip portion to beformed. In the illustrated embodiment of FIG. 9, the base iscylindrical.

The mold part 150′ further comprises a primary bevel-forming surface153, secondary bevel-forming surfaces 155, and an extension 154′. Theprimary bevel-forming surface 153 defines the shape and angle, relativeto the central axis, of the bevel face of the microneedle. The secondarybevel-forming surfaces 155 define the shape of the secondary bevels andthe angle of the secondary bevels relative to the bevel face of themicroneedle.

The extension 154′ defines the shape (e.g., circular) and size of theopening in the bevel face and also defines the shape (e.g., cylindrical)and diameter of the hollow channel in the microneedle. In anyembodiment, the microneedle may comprise a hollow channel that extendsonly partially through the body of the microneedle (i.e., the hollowchannel is a dead-end channel). In these embodiments, the extension 154′may also define the depth of the hollow channel that is made using themold part 150′. In any embodiment, an article according to the presentdisclosure may comprise hollow microneedles having a hollow channel thatextends from one side of the article to another (e.g., to a reservoirlocated on the side opposite the microneedles, not shown).

In contrast to the mold part 150 of FIG. 3, the extension 154′ of moldpart 150′ further comprises a protrusion 156 that increases the size ofthe opening created by the opening that is created by the mold part150′. The protrusion is truncated at rim 157, which defines a portion ofthe shape of the second channel (see second channel 176 of FIG. 4) ofthe microneedle formed using the mold part 150′. In any embodiment, therim 157 may be oriented substantially perpendicular to the central axisof the microneedle to be formed using the mold part 150′. In anyembodiment, the rim 157 may comprise a radius of curvature.

In any embodiment, the bevel face of a microneedle according to thepresent disclosure defines a plane. In any embodiment, the plane is aflat plane. In any embodiment, the plane may be curved or slightlycurved. In any embodiment, the bevel face may comprise a plurality ofnonparallel planes (e.g. the bevel face may comprise a dihedral bevelface, as described in U.S. Provisional Patent Application No.61/846,934, filed Jul. 16, 2013 which is incorporated herein byreference in its entirety.

Hollow microneedles of the present disclosure can be made using moldingprocesses that are known in the art. U.S. Provisional Patent ApplicationNo. 61/740,941, which is incorporated herein by reference in itsentirety, for example describes the formation of microneedles using amolding process. FIG. 10 shows a schematic view of an apparatus for usein a molding process to make hollow microneedles of the presentdisclosure. As described in the Examples herein, a first mold halfcomprising a mold cavity part 190 and the mold part 150′ of FIGS. 9A-Cis positioned proximate a second mold half 191, thereby creating acavity 195 having the shape of the one or more hollow microneedle andthe article from which the hollow microneedle projects (see FIG. 1, forexample). The mold part 150′ comprises the extension 154′ which, inconcert with protrusion 156, defines the opening and first channelproximate the tip of the formed microneedle. Optionally, the second moldhalf 191 comprises a projection 253 that defines the size and shape of ahollow channel that extends completely through the formed article. Asdescribed in U.S. Provisional Patent Application No. 61/740,941, themicroneedles are formed in such a manner that results in a hollowchannel extending completely through the body of the microneedle. In anyembodiment, certain processes (e.g., laser drilling) are used subsequentto the molding in order to complete the hollow channel.

In another aspect, the present disclosure provides a method of making anarticle comprising at least one hollow microneedle that comprises a bodyhaving a central axis, a body diameter, a base, a tip portion, and ahollow channel. The method comprises providing a first mold halfcomprising at least one cavity. The at least one cavity includes acavity opening and a cavity surface having a first projection extendingtherefrom toward the cavity opening. The first projection defines afirst segment of the hollow channel, the first segment extending intothe body of the microneedle from the base. The first projectioncomprises a first longitudinal axis. The method further comprisesproviding a second mold half comprising at least one second projectionextending therefrom. The at least one second projection defines a tipportion of the at least one microneedle and a second segment of thehollow channel, the second segment extending into the body of themicroneedle from a bevel opening proximate the tip of the at least onemicroneedle. The at least one second projection comprises a secondlongitudinal axis. The second projection is shaped and dimensioned todefine the tip portion, as described herein. The method furthercomprises contacting at least the first mold half or the second moldhalf with moldable material (e.g., polymeric material, thermoplasticpolymeric material), inserting the at least one second projection intothe cavity opening so that the first projection is substantially alignedwith the second projection, and forming the article. In any embodiment,after forming the article, the second projection causes the tip portionof the at least one microneedle to comprise a tip, a bevel face orienteddiagonally with respect to the central axis and an opening that isformed by the merging of two channels that extend into the tip portionof the hollow microneedle. The first channel extends axially into themicroneedle and the second channel extends radially, in an orientationthat is substantially orthogonal to the central axis, from the firstchannel to the opening. In any embodiment, the second projection isinserted into the at least one cavity before contacting at least thefirst mold half or the second mold half with the moldable material.Alternatively, in any embodiment, at least the first mold half or thesecond mold half is contacted with the moldable material beforeinserting the second projection into the at least one cavity.

In any of the above embodiments of the method, the at least one cavityhas a cavity aspect ratio (cavity length to cavity base width) of atleast 1.5 to 1. In any of the above embodiments of the method, the firstmold half comprises a plurality of the at least one cavities, whereinthe second mold half comprises a plurality of the at least one secondprojections, wherein the plurality of second projections is aligned tobe inserted simultaneously into the plurality of cavities.

Microneedle articles that are made according to the present disclosurecan have a variety of configurations and features, such as thosedescribed in the following patents and patent applications, thedisclosures of which are incorporated herein by reference in theirentirety. One embodiment for the microneedle articles includes thestructures disclosed in U.S. Pat. No. 6,312,612 (Sherman et al.), whichdescribes tapered structures having a hollow central channel. Yet stillanother embodiment for the microneedle array articles includes thestructures disclosed in U.S. Pat. No. 6,379,324 (Gartstein et al.),which describes hollow microneedles having at least one longitudinalblade at the top surface of the tip of the microneedle. A furtherembodiment for the microneedle array articles includes the structuresdisclosed in U.S. Patent Application Publication Nos. US2012/0123387(Gonzalez et al.) and US2011/0213335 (Burton et al.), which bothdescribe hollow microneedles. A still further embodiment for themicroneedle array articles includes the structures disclosed in U.S.Pat. No. 6,558,361 (Yeshurun) and U.S. Pat. No. 7,648,484 (Yeshurun etal.), which both describe hollow microneedle arrays and methods ofmanufacturing thereof.

Various embodiments of features of microneedles that can be employed inthe microneedle articles of the present disclosure are described in PCTPublication No. WO 2012/074576 (Duan et al.), which describes liquidcrystalline polymer (LCP) microneedles; and PCT Publication No. WO2012/122162 (Zhang et al.), which describes a variety of different typesand compositions of microneedles that can be employed in themicroneedles of the present disclosure.

Articles comprising hollow microneedles having features according to thepresent disclosure can be made, for example, by injection moldingprocesses that are known in the art. In some embodiments, themicroneedle material can be (or include) a metal, a ceramic, or apolymeric material, preferably a medical grade polymeric material. Themicroneedle material can be (or include) silicon or a metal such asstainless steel, titanium, or nickel titanium alloy. Exemplary types ofmedical grade polymeric materials include polycarbonate, liquidcrystalline polymer (LCP), polyether ether ketone (PEEK), cyclic olefincopolymer (COC), polybutylene terephthalate (PBT). Preferred types ofmedical grade polymeric materials include polycarbonate and LCP.

The microneedle articles of the present disclosure can be manufacturedin any suitable way such as by injection molding, compression molding,metal injection molding, stamping, photolithography, or extrusion. Inany embodiment, hollow microneedle arrays can be made by injectionmolding of a polymer such as medical grade polycarbonate or LCP,followed by laser drilling to form the channels of the hollowmicroneedles. Nonlimiting examples of molding processes for moldingpolymeric materials into solid microneedle articles can be found in U.S.Pat. No. 8,088,321 (Ferguson et al.) and U.S. Patent ApplicationPublication Nos. 2012/0258284 (Rendon) and 2012/0041337 (Ferguson etal.), each of which is incorporated herein by reference in its entirety.A non-limiting example of a publication that discloses the formation ofhollow channels in articles comprising microneedles is U.S. ProvisionalPatent Application No. 61/746,198, which is incorporated herein byreference in its entirety.

In some embodiments, the microneedle material can be (or include) abiodegradable polymeric material, preferably a medical gradebiodegradable polymeric material. Exemplary types of medical gradebiodegradable materials include polylactic acid (PLA), polyglycolic acid(PGA), PGA and PLA copolymer, polyester-amide polymer (PEA).

In some embodiments, the hollow microneedles can be a prepared from adissolvable, degradable, or disintegradable material referred to hereinas “dissolvable microneedles”. A dissolvable, degradable, ordisintegradable material is any solid material that dissolves, degrades,or disintegrates during use. In particular, a “dissolvable microneedle”dissolves, degrades, or disintegrates sufficiently in the tissueunderlying the stratum corneum to allow a therapeutic agent to bereleased into the tissue. The therapeutic agent may be coated on orincorporated into a dissolvable microneedle. In some embodiments, thedissolvable material is selected from a carbohydrate or a sugar. In someembodiments, the dissolvable material is polyvinyl pyrrolidone (PVP). Insome embodiments, the dissolvable material is selected from the groupconsisting of hyaluronic acid, carboxymethylcellulose,hydroxypropylmethylcellulose, methylcellulose, polyvinyl alcohol,sucrose, glucose, dextran, trehalose, maltodextrin, and a combinationthereof.

In any embodiment, the hollow microneedles can be made from (or include)a combination of two or more of any of the above mentioned materials.For example, the tip of a microneedle may be a dissolvable material,while the remainder of the microneedle is a medical grade polymericmaterial.

A microneedle or the plurality of hollow microneedles in amicroneedle-containing article of the present disclosure can have avariety of shapes that are capable of piercing the stratum corneum. Insome of the embodiments, one or more of the plurality of microneedlescan have a square pyramidal shape, triangular pyramidal shape, steppedpyramidal shape, conical shape, microblade shape, or the shape of ahypodermic needle. In any embodiment, one or more of the plurality ofmicroneedles can have a square pyramidal shape. In any embodiment, oneor more of the plurality of microneedles can have a triangular pyramidalshape. In any embodiment, one or more of the plurality of microneedlescan have a stepped pyramidal shape. In any embodiment, one or more ofthe plurality of microneedles can have a conical shape. In anyembodiment, one or more of the plurality of microneedles can have theshape of a hypodermic needle. In any embodiment, a microneedle arrayarticle may comprise an array of microneedles having a combination ofany two or more of the foregoing microneedle shapes. The shape of anymicroneedle in the microneedle array article can be symmetric orasymmetric. The shape of any microneedle in the microneedle arrayarticle can be truncated (for example, the plurality of microneedles canhave a truncated pyramid shape or truncated cone shape). In a preferredembodiment, each microneedle of the plurality of microneedles in amicroneedle array article has a square pyramidal shape.

In any embodiment, each microneedle of the plurality of microneedles ina microneedle array article is a hollow microneedle (that is, themicroneedle contains a hollow bore through the microneedle). The hollowbore can be from the base of the microneedle to the tip of themicroneedle or the bore can be from the base of the microneedle to aposition offset from the tip of the microneedle. In any embodiment, oneor more of the plurality of hollow microneedles in a hollow microneedlearray can have a conical shape, a cylindrical shape, a square pyramidalshape, a triangular pyramidal shape, or the shape of a hypodermicneedle.

In any embodiment, one or more microneedle of the plurality of hollowmicroneedles in a hollow microneedle array article can have a conicalshape; optionally, with a radius of curvature. In any embodiment, one ormore microneedle of the plurality of hollow microneedles in a hollowmicroneedle array article can have a cylindrical shape. In anyembodiment, one or more microneedle of the plurality of hollowmicroneedles in a hollow microneedle array article can have a segmenthaving a square pyramidal shape. In any embodiment, one or moremicroneedle of the plurality of hollow microneedles in a hollowmicroneedle array article can have a segment having a triangularpyramidal shape. In any embodiment, one or more microneedle of theplurality of hollow microneedles in a hollow microneedle array articlecan have a segment having the shape of a hypodermic needle. In apreferred embodiment, each microneedle of the plurality of hollowmicroneedles in a hollow microneedle array article has a segment withthe shape of a conventional hypodermic needle.

In any embodiment, an article comprising a hollow microneedle accordingto the present disclosure may comprise a plurality of the microneedles.The plurality of the microneedles optionally may form an array. In anyembodiment, the article can comprise an array of about 3 to about 30,inclusive, of the hollow microneedles of the present disclosure. In apreferred embodiment, the article can comprise an array of about 8 toabout 20, inclusive, of the hollow microneedles of the presentdisclosure. In a more-preferred embodiment, the article can comprise anarray of 12, 16, or 18 of the hollow microneedles of the presentdisclosure.

In any embodiment of an article comprising a plurality of hollowmicroneedles according to the present disclosure, the overall height ofeach microneedle is about 400 μm to about 3000 μm. In any embodiment ofan article comprising a plurality of hollow microneedles according tothe present disclosure, the overall height of each microneedle is about400 μm to about 2000 μm. In any embodiment of an article comprising aplurality of hollow microneedles according to the present disclosure,the overall height of each microneedle is about 750 μm to about 1600 μm.

In any embodiment of an article comprising a plurality of hollowmicroneedles according to the present disclosure, a hollow channelextending through each of the microneedles has a diameter, proximate thetip of the microneedle, of about 10 μm to about 200 μm. In anyembodiment of an article comprising a plurality of hollow microneedlesaccording to the present disclosure, a hollow channel extending througheach of the microneedles has a diameter, proximate the tip of themicroneedle, of about 10 μm to about 120 μm. In any embodiment of anarticle comprising a plurality of hollow microneedles according to thepresent disclosure, a hollow channel extending through each of themicroneedles has a diameter, proximate the tip of the microneedle, ofabout 25 μm to about 75 μm.

In any embodiment of an article comprising a plurality of hollowmicroneedles according to the present disclosure, a hollow channelextending through each of the microneedles has a cross-sectional area ofabout 75 μm² to about 32,000 μm². In any embodiment of an articlecomprising a plurality of hollow microneedles according to the presentdisclosure, a hollow channel extending through each of the microneedleshas a cross-sectional area of about 75 μm² to about 18,000 μm². In anyembodiment of an article comprising a plurality of hollow microneedlesaccording to the present disclosure, a hollow channel extending througheach of the microneedles has a cross-sectional area of about 700 μm² toabout 3,000 μm².

The hollow microneedle array articles of the present disclosure can bemanufactured by injection molding of a polymer such as medical gradepolycarbonate or LCP. Typically, these processes use molds to form thesubstrate with the microneedles extending therefrom.

Microneedles of the present disclosure advantageously provide a largeropening, with respect to a predetermined microneedle wall thickness,than can be attained using conventional process known in the art. Thelarger opening facilitates the delivery of material (e.g.,pharmaceutically-active compositions) from the hollow channel of themicroneedle into the skin tissue and underlying layers of tissue. FIG.11 shows the area 185 defined by a conventional opening in a hollowmicroneedle. Typically, a conventional opening is created by bisectingthe body of the microneedle with a bevel face and the area 185represents the cross-sectional area of the opening that is created alongthe bevel face. FIG. 11 also shows the additional area 186 that isgained by making a microneedle according to the present disclosure.

In addition, using a process according to the present disclosure, themicroscopic mold parts that are used to form the tip portion of theneedle are significantly less susceptible to damage during extended usebecause the extensions that form the tip-proximal hollow channel in themicroneedle are made stronger by the presence of the protrusion thatforms the second bevel face.

Any of the above embodiments of a microneedle according to the presentdisclosure can be used for injecting fluid into a body. Any of the aboveembodiments of a microneedle according to the present disclosure can beused for extracting fluid from a body.

Exemplary Embodiments

Embodiment A is an article, comprising:

at least one microneedle, the at least one microneedle comprising:

-   -   a base;    -   an elongated body having a central axis;    -   a tip portion comprising a tip, a beveled surface, and a bevel        opening in the beveled surface;    -   a first channel that extends axially from the bevel opening        through at least a portion of the elongated body, wherein the        first channel has a first wall that is substantially aligned        with the central axis; and    -   a second channel that extends radially from the first channel to        the bevel opening, wherein the second channel has a second wall        that is oriented substantially orthogonal to the central axis;    -   wherein the first channel and second channel merge to form the        bevel opening.

Embodiment B is the article of Embodiment A, wherein the article furthercomprises a substrate having a first side and a second side, wherein theat least one microneedle extends from the first side of the substrate,wherein the first channel extends from the bevel opening through theelongated body to a second opening on the second side of the substrate.

Embodiment C is the article of Embodiment A or Embodiment B, wherein theat least one microneedle comprises a plurality of microneedles.

Embodiment D is the article of any one of the preceding Embodiments,wherein the bevel opening is an elongated opening comprising a first endproximate the tip and a second end proximate the base.

Embodiment E is the article of any one of Embodiments A through D,wherein the beveled surface is defined by a bevel edge surrounding thebeveled surface, wherein the opening is defined by an opening edgesurrounding the opening, wherein no portion of the opening edge iscoincident with any portion of the bevel edge.

Embodiment F is the article of any one of Embodiments A through D,wherein the beveled surface is defined by a bevel edge surrounding thebeveled surface, wherein the opening is defined by an opening edgesurrounding the opening, wherein at least a portion of the opening edgeis coincident with a portion of the bevel edge.

Embodiment G is the article of any one of the preceding Embodiments,wherein the tip portion comprises plurality of intersecting planes.

Embodiment H is the article of any one of the preceding Embodiments,wherein the bevel face defines a first plane, wherein a firsttwo-dimensional area defined by the bevel opening is larger than asecond two-dimensional area defined by a cross-sectional area of thefirst channel taken along the first plane.

Embodiment I is a use of the article of any one of Embodiments A throughH for injecting fluid into a body.

Embodiment J is a use of the article of any one of Embodiments A throughH for removing fluid from a body.

Embodiment K is a method of making an article comprising at least onemicroneedle that comprises an elongated body having body diameter, abase, a tip portion, and a hollow channel extending from the base to thetip portion; the method comprising:

-   -   providing a first mold half comprising at least one cavity;        -   wherein the at least one cavity includes a cavity opening            and a cavity surface having a first projection extending            therefrom toward the cavity opening;        -   wherein the first projection defines a first segment of the            hollow channel, the first segment extending into the body of            the microneedle from the base;        -   wherein the first projection comprises a first longitudinal            axis;    -   providing a second mold half comprising at least one second        projection extending therefrom;        -   wherein the at least one second projection defines a tip            portion of the microneedle and a second segment of the            hollow channel, the second segment extending into the body            of the microneedle from a bevel opening proximate the tip of            the at least one microneedle;        -   wherein the at least one second projection comprises a            second longitudinal axis;        -   wherein the second projection is shaped and dimensioned to            define the tip portion;            -   wherein the tip portion includes a tip, a beveled                surface, a bevel opening in the bevel surface, a first                channel that extends axially from the bevel opening                through at least a portion of the elongated body, and a                second channel            -   wherein the first channel has a first wall that is                substantially aligned with the second longitudinal axis;                and            -   wherein the second channel has a second wall that is                oriented substantially orthogonal to the second                longitudinal axis;        -   wherein the second projection is shaped and dimensioned such            that the first channel and second channel merge to form the            bevel opening;        -   contacting at least the first mold surface or the second            mold surface with polymeric material; and        -   inserting the second projection into the at least one            cavity.

Embodiment L is the method of Embodiment K, wherein the secondprojection is inserted into the at least one cavity before contacting atleast the first mold surface or the second mold surface with themoldable material.

Embodiment M is the method of Embodiment K, wherein at least the firstmold surface or the second mold surface is contacted with the moldablematerial before inserting the second projection into the at least onecavity.

Embodiment N is the method of any one of Embodiments K through M,wherein the moldable material comprises a metal, a ceramic material, ora polymeric material.

Embodiment O is the method of any one of Embodiments K through N,wherein the at least one cavity has a cavity aspect ratio (cavity lengthto cavity base width) of at least 1.5 to 1.

Embodiment P is the method of any one of Embodiments K through), whereinthe first mold half comprises a plurality of the at least one cavities,wherein the second mold half comprises a plurality of the at least onesecond projections, wherein the plurality of second projections isaligned to be inserted simultaneously into the plurality of cavities.

EXAMPLES Example 1 Fabrication of Microneedle Articles

The microneedle articles were prepared from polymeric material usingstandard injection molding procedures. The molded microneedle articleswere prepared using a mold assembly prepared from three mold sectionswith each section machined from steel. The first mold section containedprojections that defined the beveled shape of the needle tip in themolded array. Each projection in the first mold section had a furthercylindrical extension that defined features of the tip segment of themicroneedles tip, including the opening on a bevel proximate the tip ofthe microneedle and a portion of the hollow channel extending throughthe body of each microneedle. The second mold section served as atemplate to define the pattern of the microneedles in the moldedarticle, the external shape and size of the microneedles in the moldedarticle, and the first side of the article (including the central cavityportion, platform portion, and peripheral portion, as described above).The third mold section contained cylindrical projections emerging from aplanar surface with each projection defining a second (base-proximal)part of the microneedle hollow channel and the opening located at thebase of each microneedle in the molded article. The planar surface fromwhich the projections emerged served to define the second major surfaceof the base segment of the molded article. The first and second moldsections were assembled to form a tight fit by inserting the projectionsof the first mold section into the corresponding openings in the secondmold section. The assembled first and second mold sections formed thefirst mold half. The third mold section was used as the second moldhalf.

The first and second mold halves were installed in a mold base in a60-ton injection molding press (Sodick Plustech LA 60, Sodick PlustechCo., Yokohama, Japan). As is common in the art, the parting line of themold assembly had both primary and secondary vents for general airevacuation during injection of the polymeric material. Vectra MT1300liquid crystal polymer (LCP) pellets (Ticona Engineering Polymers,Florence, Ky.) were loaded into a reciprocating screw and heated untilmolten. The first mold half and second mold half were heated to atemperature (hereafter referred to as the “mold temperature atinjection”) of 200° F. (93.3° C.). The molding cycle was initiated byclosing the first mold half with the second mold half. The molds wereclamped together with approximately 20 to 60 tons of force. In theclamped position, the surfaces at the tips of the projections in thesecond mold half were aligned with and in contact with the surfaces atthe tips of the projections in the first mold half. A first portion(approx. 50-95% of the part size volume) of the total amount of materialfrom the reciprocating screw was injected into the mold chamber at afixed velocity (hereafter referred to as the “injection velocity”) ofabout 7 inches/second (17.8 cm/second). After injecting the firstportion of material, the process was switched from an injection-drivento a pressure-driven mode by applying a fixed pressure (hereafterreferred to as the “pack pressure”) of about 13,500 psi (93,079kilopascal) to force the remainder of the molten material into thenegative mold insert. The pack pressure was applied for a fixed time(hereafter referred to as the “hold time”) of 5 seconds. The packpressure was subsequently released and the mold chamber was cooled to anejection temperature set below the softening temperature of LCP. Themold chamber was opened and the microneedle article was ejected.

Example 2 Injection Apparatus Used to Test the Microneedle Articles

Fully assembled microneedle article injection apparatuses similar toapparatuses described in U.S. Patent Application Publication No.US2012/0123387 (FIGS. 1-13) and U.S. Provisional Patent Application No.61/740,941 (FIGS. 2, 14 and 15) were used. The drug cartridge in eachapparatus contained al mL solution of 0.005% methylene blue in fivepercent aqueous dextrose. The injection apparatus from Example 1 of U.S.Provisional Patent Application No. 61/740,941 was used with thefollowing exceptions. First, the section of the apparatus joined to theadhesive assembly was not milled to remove material. Second, theconstruction of the adhesive assembly was different. Instead of usingthe four layer adhesive of U.S. Provisional Patent Application No.61/740,941, the adhesive assembly used was a laminate composed of onlytwo layers. The first layer was a 0.10 mm thick sheet of 3M 1510 doublesided tape (available from the 3M Company). The second layer was a 0.07mm sheet of 3M 1524 transfer adhesive. The two layer adhesive assemblywas positioned to cover the first major surface of base member of thelower housing at the rounded end section of the device. The adhesiveassembly laminate was laser cut so that the size and shape of theadhesive assembly was matched to that of the device. The two layers ofthe adhesive assembly each contained cut-out regions that were alignedto each other and exactly matched the opening in the device housing. Thedevice and adhesive assembly were oriented so that the first layer ofthe adhesive assembly was adhered to the lower housing of the device.The adhesive assembly was aligned with the device so that the opening inthe first layer of the adhesive assembly was coincident with the openingin the device. A release liner was used during storage of the device toprotect the exposed adhesive of the second layer of the adhesiveassembly.

The hollow microneedle article used in the microneedle article injectionapparatus (as shown in FIG. 1) was molded (as described in Example 1)from Vectra MT1300 liquid crystal polymer (LCP) in the shape of a circleapproximately 1.25 cm in diameter. The circular platform portionprojected about 1.0 mm from the outside edge of the article and theperipheral portion canted away from the platform portion with a 36.9degree cant, relative to the plane of the platform portion. The closedcircular cavity of the article was centered on the article with adiameter of about 6.8 mm defined by the circular region formed by theinner perimeter of the platform), a depth of about 500 microns at thecenter of the cavity, and a radius of curvature of about 11 mm. Thediameter of the circular region formed by the outer perimeter of theplatform was about 10.3 mm. The width of the platform was about 1.75 mm.The article featured a linear array of 12 hollow microneedles extendingfrom the circular platform portion of the article. The microneedles wereevenly spaced with the distance between neighboring microneedles beingabout 2.2 mm (as measured from tip to tip). Each microneedle wasoriented so that the opening at the tip was facing toward the outerperimeter of the article along a radial vector. The external diameter ofeach microneedle at the base was about 1.5 mm. The flared base segmentof each microneedle had a radius of curvature of about 1 mm. The tipsegment of each microneedle was in the shape of a conventionalhypodermic needle with a 33.6 degree bevel and a chamfered tip that hadan included angle of 70 degrees. The opening near the tip was obround inshape (as shown in FIG. 5) with dimensions of 303 microns by 80 microns.Each microneedle had a total height of about 1500 microns as measuredfrom the base of the microneedle at the platform surface to the tip ofthe microneedle. The distance from the tip of each microneedle to thecenter of the opening near the tip was about 382 microns. The averagediameter of the hollow channel proximate the tip of each microneedle wasabout 80 microns.

Example 3 Injection Apparatus

The same microneedle injection apparatus as described in Example 2 wasused with the exception that the wire diameter of the U-shaped leaf-likeinsertion spring (i.e. first stored energy device as described in U.S.Patent Application Publication No. US2012/0123387 (FIGS. 1-13) and U.S.Provisional Patent Application No. 61/740,941 (FIGS. 2, 14 and 15)) was1.50 mm instead of 1.59 mm.

Example 4 Alternative Injection Apparatus

The same microneedle injection apparatus as described in Example 2 wasused with the exception that the wire diameter of the U-shaped leaf-likeinsertion spring (i.e. first stored energy device as described in U.S.Patent Application Publication No. US2012/0123387 (FIGS. 1-13) and U.S.Provisional Patent Application No. 61/740,941 (FIGS. 2, 14 and 15)) was1.40 mm instead of 1.59 mm.

Example 5 Use of Microneedle Article to Inject a Substance

The study was conducted using Yorkshire cross domestic pigs (MidwestResearch Swine, Gibbon, Minn.) in vivo. A soft region of the bellyhaving minimal muscle content was selected as the application site formicroneedle insertion. The application site was first trimmed with anelectric clipper and then shaved using a razor and shaving cream. Theshaved area was scrubbed using soapy water and a BUF-PUF exfoliationsponge (3M Company, St. Paul, Minn.) and then rinsed with deionizedwater. The animal was placed in a lateral recumbent position on a heatedtable (38° C.). The animal was anesthetized with isofluorene gas andmaintained under anesthesia throughout the experiment. The applicationsite was then wiped with a 70% isopropanol in water solution.

The injection apparatus of Example 4 was used. The release liner wasremoved from the adhesive assembly and the apparatus was adhered to theskin of the pig. During attachment of the device to the pig, the skin atthe application site was gently stretched to provide a slight tension tothe skin. The skin was then allowed to relax and the push-button wasdepressed to cause release of the applicator element and insertion ofthe microneedle article into the skin of the pig. Removal of the taperedpin from the housing released the coiled spring which initiated theinjection of the methylene blue solution into the pig. After completionof the injection, the apparatus was maintained on the skin for oneadditional minute. The apparatus was removed from the skin and the skinsurface was examined to determine if there was any methylene bluesolution on the surface of the skin. The presence of methylene bluesolution on the skin was an indication that not all of the methyleneblue was injected into the animal The injection site was wiped with apre-tared absorbent wipe and the wipe was then weighed to determine theamount of methylene blue that was not successfully delivered.

A total of three replicates were conducted. The injection times rangedfrom 29 to 111 seconds with the average injection time being 63 seconds.Two of the apparatuses successfully delivered the methylene bluesolution without any “leakage” (i.e. no methylene blue solution wasobserved on the skin surface). The third apparatus successfullydelivered 97% of the methylene blue solution.

Example 6 Use of Microneedle Article

A study was conducted to determine the depth of penetration (DOP) of themicroneedles of the article when applied to the skin surface of aYorkshire cross domestic pigs (Midwest Research Swine), in vivo. Thehollow microneedle article described in Example 2 was used.

The microneedles on the article were coated using a three step process.The first two steps involved applying primer coatings to themicroneedles and the third step involved applying a thin coating ofRhodamine B to the microneedles. In Step 1, the articles were floodcoated with a 35 microliter solution containing 0.5 mg/mL polyvinylalcohol (80% hydrolyzed) (Sigma-Aldrich, Inc., St. Louis, Mo.) and 35μg/ml of TWEEN® 80 (Sigma-Aldrich) in 90% (w/v) ethanol. The coatedarticles were then dried at 35° C. for 20 minutes. In Step 2, thearticles from Step 1 were flood coated with 35 microliters of an aqueoussolution of 33.3 mg/ml aluminum potassium sulfate (Penta Manufacturing,Livingston, N.J.). The coated articles were then dried at 35° C. for 30minutes. In Step 3, the primed articles from Step 2 were flood coatedwith 40 microliters of an aqueous solution of 0.08% (w/v) Rhodamine B(Sigma-Aldrich). The coated articles were dried at 35° C. for 30minutes. The three step process provided articles in which themicroneedles were completely covered with a thin, opaque coating ofRhodamine B.

The ham region was selected as the application site for microneedleinsertion. The application site was first trimmed with an electricclipper and then shaved using a razor and shaving cream. The shaved areawas scrubbed using soapy water and a BUF-PUF exfoliation sponge (3MCompany) and then rinsed with deionized water. The animal was placed ina lateral recumbent position on a heated table (38° C.). The animal wasanesthetized with isofluorene gas and maintained under anesthesiathroughout the experiment. The application site was then wiped with a70% isopropanol in water solution.

The injection apparatus described in Example 2 with a Rhodamine B coatedarticle was used. The release liner was removed from the adhesiveassembly and the apparatus was adhered to the skin of the pig. Thepush-button was depressed to cause release of the applicator element andinsertion of the microneedles of the microneedle article into the skinof the pig. The injection apparatus was maintained on the skin for anadditional 5 minutes.

The injection apparatus was removed from the animal. The depth ofpenetration (DOP) of the microneedles into the pig skin was determinedindirectly by measuring the distance from the tip of the microneedle towhere the Rhodamine B coating was wiped or dissolved from themicroneedle after application into the skin. The measurement wasconducted using a Nikon LV-100 microscope at 100× magnification (NikonInstruments, Melville, N.Y.) with Image Pro® Plus digital image analysissoftware (Media Cybernetics, Bethesda, Md.). A total of two replicateswere conducted. The mean microneedle DOP was determined by sampling allof the microneedles from each article (n=24). The results are presentedin Table 1.

TABLE 1 Depth of Penetration (DOP) when Microneedle Article was Appliedto the Ham Area (Example 6). Minimum DOP 729 microns Maximum DOP 901microns Mean DOP (n = 32) 827 microns Standard Deviation  48 microns %RSD 6%

Example 7 Use of Microneedle Article

The procedure as described in Example 6 was used with the exception thatthe injection apparatus of Example 3 was used instead of the injectionapparatus of Example 2. The results are presented in Table 2.

TABLE 2 Depth of Penetration (DOP) when Microneedle Article was Appliedto the Ham Area (Example 7). Minimum DOP 558 microns Maximum DOP 849microns Mean DOP (n = 24) 751 microns Standard Deviation  74 microns %RSD 10%

Example 8

Use of Microneedle Article

The procedure as described in Example 6 was used with the exception thatthe injection apparatus of Example 4 was used instead of the injectionapparatus of Example 2. The results are presented in Table 3.

TABLE 3 Depth of Penetration (DOP) when Microneedle Article was Appliedto the Ham Area (Example 8) Minimum DOP 709 microns Maximum DOP 863microns Mean DOP 787 microns Standard Deviation  45 microns % RSD 6%

The complete disclosure of all patents, patent applications, andpublications, and electronically available material cited herein areincorporated by reference. In the event that any inconsistency existsbetween the disclosure of the present application and the disclosure(s)of any document incorporated herein by reference, the disclosure of thepresent application shall govern. The foregoing detailed description andexamples have been given for clarity of understanding only. Nounnecessary limitations are to be understood therefrom. The invention isnot limited to the exact details shown and described, for variationsobvious to one skilled in the art will be included within the inventiondefined by the claims.

All headings are for the convenience of the reader and should not beused to limit the meaning of the text that follows the heading, unlessso specified.

Various modifications may be made without departing from the spirit andscope of the invention. These and other embodiments are within the scopeof the following claims.

1. An article, comprising: at least one microneedle, the at least onemicroneedle comprising: a base; an elongated body having a central axis;a tip portion comprising a tip, a beveled surface, and a bevel openingin the beveled surface; a first channel that extends axially from thebevel opening through at least a portion of the elongated body, whereinthe first channel has a first wall that is substantially aligned withthe central axis; and a second channel that extends radially from thefirst channel to the bevel opening, wherein the second channel has asecond wall that is oriented substantially orthogonal to the centralaxis; wherein the first channel and second channel merge to form thebevel opening.
 2. The article of claim 1, wherein the article furthercomprises a substrate having a first side and a second side, wherein theat least one microneedle extends from the first side of the substrate,wherein the first channel extends from the bevel opening through theelongated body to a second opening on the second side of the substrate.3. The article of claim 1, wherein the at least one microneedlecomprises a plurality of microneedles.
 4. The article of claim 1,wherein the bevel opening is an elongated opening comprising a first endproximate the tip and a second end proximate the base.
 5. The article ofclaim 1, wherein the beveled surface is defined by a bevel edgesurrounding the beveled surface, wherein the opening is defined by anopening edge surrounding the opening, wherein no portion of the openingedge is coincident with any portion of the bevel edge.
 6. The article ofclaim 1, wherein the beveled surface is defined by a bevel edgesurrounding the beveled surface, wherein the opening is defined by anopening edge surrounding the opening, wherein at least a portion of theopening edge is coincident with a portion of the bevel edge.
 7. Thearticle of claim 1, wherein the tip portion comprises plurality ofintersecting planes.
 8. The article of claim 1, wherein the bevel facedefines a first plane, wherein a first two-dimensional area defined bythe bevel opening is larger than a second two-dimensional area definedby a cross-sectional area of the first channel taken along the firstplane.
 9. A use of the article, as claimed in claim 1, for injectingfluid into a body.
 10. A use of the article, as claimed in claim 1, forextracting fluid from a body.
 11. A method of making an articlecomprising at least one microneedle that comprises an elongated bodyhaving body diameter, a base, a tip portion, and a hollow channelextending from the base to the tip portion; the method comprising:providing a first mold half comprising at least one cavity; wherein theat least one cavity includes a cavity opening and a cavity surfacehaving a first projection extending therefrom toward the cavity opening;wherein the first projection defines a first segment of the hollowchannel, the first segment extending into the body of the microneedlefrom the base; wherein the first projection comprises a firstlongitudinal axis; providing a second mold half comprising at least onesecond projection extending therefrom; wherein the at least one secondprojection defines a tip portion of the microneedle and a second segmentof the hollow channel, the second segment extending into the body of themicroneedle from a bevel opening proximate the tip of the at least onemicroneedle; wherein the at least one second projection comprises asecond longitudinal axis; wherein the second projection is shaped anddimensioned to define the tip portion; wherein the tip portion includesa tip, a beveled surface, a bevel opening in the bevel surface, a firstchannel that extends axially from the bevel opening through at least aportion of the elongated body, and a second channel that extendsradially from the first channel to the bevel opening; wherein the firstchannel has a first wall that is substantially aligned with the secondlongitudinal axis; and wherein the second channel has a second wall thatis oriented substantially orthogonal to the second longitudinal axis;wherein the second projection is shaped and dimensioned such that thefirst channel and second channel merge to form the bevel opening;contacting at least the first mold surface or the second mold surfacewith moldable material; and inserting the second projection into the atleast one cavity.
 12. The method of claim 11, wherein the secondprojection is inserted into the at least one cavity before contacting atleast the first mold surface or the second mold surface with themoldable material.
 13. The method of claim 11, wherein at least thefirst mold surface or the second mold surface is contacted with themoldable material before inserting the second projection into the atleast one cavity.
 14. The method of claim 11, wherein the moldablematerial comprises a metal, a ceramic, or a polymeric material.
 15. Themethod of claim 11, wherein the at least one cavity has a cavity aspectratio (cavity length to cavity base width) of at least 1.5 to
 1. 16. Themethod of claim 11, wherein the first mold half comprises a plurality ofthe at least one cavities, wherein the second mold half comprises aplurality of the at least one second projections, wherein the pluralityof second projections is aligned to be inserted simultaneously into theplurality of cavities.